Evolution, mechanisms, and classification of antiarrhythmic drugs: focus on class III actions

Since the use of cinchona bark to treat heart palpitations in the 1700s, antiarrhythmic drug therapy has developed with the discovery of new compounds and the identification of ionic, cellular, and tissue mechanisms of action. Classifications have been developed that organize the large amount of information available about antiarrhythmic drugs around groups of compounds with common mechanisms of action. Despite important and well-recognized limitations, antiarrhythmic drug classification is still widely used. In particularly broad use is the system developed by Singh and Vaughan Williams in the early 1970s and subsequently modified by Singh and Hauswirth and by Harrison. This classification divides drug actions into class I for sodium-channel blockade (with subclasses IA, IB and IC), class II for adrenergic antagonism, class III for action-potential prolongation, and class IV for calcium-channel blockade. The development of class I drugs was curtailed when studies showed that potent sodium-channel blockers (particularly IC agents) can increase mortality in patients with active coronary artery disease. The emphasis in drug development shifted to class III agents, but their use has been limited by the risk of ventricular tachyarrhythmia induction associated with QT prolongation. Current research focuses on the development of new class III drugs that may have improved safety by virtue of greater selectivity of action at faster rates (like those of arrhythmia) or for atrial tissue. Alternative approaches include the modification of existing molecules (like amiodarone) to maintain positive properties while removing undesirable ones, and treatments that target development of the arrhythmia substrate instead of the final electrical product.